title: Production of ramoplanin analogues by genetic engineering of Actinoplanes sp.
abstract: Ramoplanins are lipopeptides effective against a wide range of Gram-positive pathogens. Ramoplanin A2 is in Phase III clinical trials. The structure-activity relationship of the unique 2Z,4E-fatty acid side-chain of ramoplanins indicates a significant contribution to the antimicrobial activities but ramoplanin derivatives with longer 2Z,4E-fatty acid side-chains are not easy to obtain by semi-synthetic approaches. To construct a strain that produces such analogues, an acyl-CoA ligase gene in a ramoplanin-producing Actinoplanes was inactivated and a heterologous gene from an enduracidin producer (Streptomyces fungicidicus) was introduced into the mutant. The resulting strain produced three ramoplanin analogues with longer alkyl chains, in which X1 was purified. The MIC value of X1 was ~0.12 μg/ml against Entrococcus sp. and was also active against vancomycin-resistant Staphylococcus aureus (MIC = 2 μg/ml).
authors.affiliation: State Key Laboratory of New Drug and Pharmaceutical Process, Shanghai Institute of Pharmaceutical Industry, 1320 West Beijing Road, Shanghai, 200040, China.
authors.forename: Hai-Xue
authors.initials: HX
authors.lastname: Pan
authors.forename: Zhou-Zhou
authors.initials: ZZ
authors.lastname: Chen
authors.forename: Lei
authors.initials: L
authors.lastname: Shao
authors.forename: Ji-An
authors.initials: JA
authors.lastname: Li
authors.forename: Jun-Sheng
authors.initials: JS
authors.lastname: Chen
authors.forename: Chun-Bao
authors.initials: CB
authors.lastname: Zhu
authors.forename: Gong-Li
authors.initials: GL
authors.lastname: Tang
authors.forename: Dai-Jie
authors.initials: DJ
authors.lastname: Chen
mesh_terms: D000900:Anti-Bacterial Agents / Q000378:metabolism; D047630:Depsipeptides / Q000378:metabolism*; D016983:Enterococcus / Q000187:drug effects; D060847:Metabolic Engineering; D008826:Microbial Sensitivity Tests; D008848:Micromonosporaceae / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism*; D013211:Staphylococcus aureus / Q000187:drug effects; D013302:Streptomyces / Q000201:enzymology / Q000235:genetics
chemical_list: D000900:Anti-Bacterial Agents; D047630:Depsipeptides; C041438:ramoplanin